Estimation Methods for Nonlinear ODE Models in AIDS Research Abstract In this project we propose identifiability methods and statistical estimation methods for ordinary differential equation (ODE) models to support HIV/AIDS research. Although many mathematical models and statistical methods have been developed for epidemiological and clinical studies in AIDS research, very few identifiability and estimation methods are developed for nonlinear ODE models which are widely used in AIDS research. It is challenging to estimate the parameters in the ODE models when no closed-form solution is available for nonlinear ODEs. Very few formal statistical estimation methods are available for ODE models. To fill this gap, in this project we propose novel statistical estimation methods for nonlinear ODE models derived from HIV/AIDS research. In particular, we propose four specific aims: 1) Integrate parameter identifiability techniques from different research disciplines to address the identifiability issues for ordinary differential equation (ODE) models; 2) Develop novel statistical estimation methods for ODE models and study the asymptotic and finite-sample properties of the estimators; 3) Evaluate the new methods by comparing them to the existing methods based on theoretical perspective, finite sample properties and computational efficiency, and test and validate the proposed methods using the examples and data from studies of immune response to viral infections; 4) Develop efficient computational algorithms and user-friendly software packages to implement the proposed methods. We propose several novel estimation methods including sieve-based methods for estimating both constant and time-varying parameters, penalized kernel estimation methods and numerical algorithm-based regression approaches for ODE models. The model identifiability analysis for ODE models is also relatively innovative from statistical perspective. To achieve our aims, we have formed a strong interdisciplinary research team consisting of statisticians, computational scientists and software developers with necessary expertise for this project. The differential equation models are often developed based on mechanisms of biomedical systems. The model parameters usually have meaningful biological interpretations and are important in their own rights. It is very important to reliably estimate these model parameters from experimental data. The estimation results may help HIV/AIDS investigators better understand the biological mechanisms and pathogenesis of HIV infection, which may lead to novel scientific findings and provide guidance to develop treatment strategies. PUBLIC HEALTH RELEVANCE: The developed statistical methods for ODE models of HIV dynamics and AIDS epidemics allow to reliably estimate the unknown kinetic or epidemic parameters of HIV dynamics and AIDS epidemics. These parameters and the ODE models can be used to help HIV/AIDS investigators better understand the biological mechanisms and pathogenesis of HIV infection, which may lead to novel scientific findings and provide guidance to develop treatment strategies.